1 This proposal will address gaps in our understanding of the intractable racial disparities in preterm birth 2 by focusing on maternal vitamin D status and vitamin D receptor (VDR) genetic variation. We have shown that 3 vitamin D deficiency is pervasive among pregnant black women and is significantly less common among white 4 women. Further, data indicate that vitamin D has direct and indirect influences on inflammation and other 5 known molecular pathways in the pathogenesis of preterm birth. We hypothesize that maternal vitamin D 6 deficiency at d20 weeks gestation and maternal genotypic variation in the VDR gene are associated with risk of 7 preterm birth. Novel preliminary data that we have generated as part of an NIH-funded grant (R01 HD056999, 8 PI: Bodnar) on a large cohort of U.S. pregnancies in the 1960s support this hypothesis and warrant 9 confirmation in a modern, ethnically-diverse cohort. 10 To test this hypothesis, we will conduct a nested case-control study using existing banked maternal 11 serum samples and data from a cohort of 17,027 non-Hispanic white and 6,065 non-Hispanic black women 12 who received prenatal screening and delivered singleton, live births with no fetal anomalies at Magee-Womens 13 Hospital in Pittsburgh, Pennsylvania (1999-2010). We will select all cases of preterm birth (n=1539 white and 14 n=805 black cases) and an equal number of race-matched controls for the assay maternal serum 25- 15 hydroxyvitamin D (25(OH)D) at d20 weeks gestation and genotyping. First, we will determine the independent 16 association between maternal vitamin D status at d20 weeks gestation and the risk of preterm birthoverall, as 17 well as early (<32 weeks) and late (32-<37 weeks) preterm birth, and spontaneous and indicated preterm birth. 18 Second, we will determine the contribution of maternal vitamin D status to the racial disparity in preterm birth. 19 Finally, we will determine the effect of maternal genetic variation in the vitamin D receptor gene on maternal 20 vitamin D status and on the risk of preterm birth. 21 The successful completion of these aims will address some of the most urgent research 22 recommendations from the 2010 IOM Committee on Dietary Reference Intakes for Calcium and Vitamin D, 23 including exploring the role of vitamin D in non-skeletal health outcomes of pregnancy; and elucidating the 24 effect of genetic variation, including that among racial/ethnic groups, of vitamin D on health outcomes. We are 25 ideally suited to conduct this study because of our rigorous assessment of gestational age, ability to phenotype 26 clinical subtypes of preterm birth, statistical power for subtype analyses, and large numbers of both white and 27 black women. Our research team has the existing infrastructure, proven collaboration, and significant 28 experience in the successful completion of projects related to both preterm birth and vitamin D. Because it is 29 safe, inexpensive, and straightforward to improve maternal vitamin D status in pregnancy, exploring how 30 vitamin D contributes to racial disparities in birth outcomes could have a major public health impact.